Methods of treatment using ascorbyl gamma linolenic acid or ascorbyl dihomo-gamma-linolenic acid

ABSTRACT

Optimum conditions for prostaglandin synthesis are provided by internally administering an ascorbic-6-acid ester of gamma-linolenic acid or an ascorbic-6-acid ester of dihomo-gamma-linolenic acid.

This is a division of application Ser. No. 08/828,716, filed Mar. 28,1997, now U.S. Pat. No. 5,847,000 which is a file wrapper continuationof Ser. No. 08/388,667 filed Feb. 17, 1995 now abandoned.

The invention relates to ascorbic acid (Vit. C) derivatives of fattyacids.

Ascorbic acid derivatives of fatty acids (1) are known, where R is afatty acid chain and R¹=H or R.

Thus Kaneko et al Arch. Biochm. Biophys. 304 No. 1,176-180, (1993)report protective action against the cytoxicity of linoleic acidhydroperoxide in human cell cultures, shown by 6-0-palmitoyl,6-0-stearoyl and 2,6-0-dipalmitoyl ester and 2-0-octadecyl etherderivatives of ascorbic acid. Similarly the preparation of ascorbyldocosahexaenoate has been described.

Further, unsaturated fatty acids have been protected from atmosphericoxidation by ascorbic acid used with phosphorylated mono- or di-fattyacyl glycerides, the ascorbic acid optionally being in the form of apalmitate or stearate (Cloughley, EPA 93304827.4, based on UK 9213322.2).

Also, the idea of co-administering gamma-linolenic acid (GLA) ordihomo-gamma-linolenic acid (DGLA) with ascorbic acid has been publishedin a number of previous applications by the inventors, for example EPA 0019 423 and EPA 0 085 579.

Generally however little attention has been paid to ascorbate esters offatty acids though Kanebo in JP-A-62 081307 discloses GLA esters ofascorbic acid in cosmetic compositions.

Ascorbic acid is of course well known as a water-soluble vitaminessential for health. Less remarked is the fact that ascorbic acid isable to stimulate the conversion of DGLA to prostaglandin E₁ (PGE₁).PGE₁ is a short lived substance which has an exceptionally wide range ofdesirable effects. It dilates blood vessels and bronchi and bronchioles,inhibits platelet aggregation, exerts anti-inflammatory effects, lowerscholesterol levels, lowers blood pressure, and is believed to have arange of other desirable actions including anti-cancer andanti-metastatic effects.

In view of the desirable effects of PGE₁ optimum conditions should existfor its formation in the body. One way of seeking to ensure this is toincrease intake of DGLA or its immediate precursor GLA. Another is toprovide appropriate levels of ascorbic acid to encourage the formationof PGE₁.

We now find that it is specifically advantageous to give GLA and DGLA astheir ascorbic-6-acid esters subsequently referred to as Ascorbyl GLAand Ascorbyl DGLA. These compounds can be synthesised by the reaction ofthe acid chloride or anhydride of the fatty acid in the presence of amineral acid catalyst i.e. hydrogen chloride, in a suitable solvent e.g.dimethyl acetamide/dichloromethane at a temperature between −10° C. and30° C. as described herein. They have pharmaceutical uses in manyconditions and the invention extends to their use in such conditions andin the preparation of medicaments for the purpose. The conditionsinclude:

(a) asthma and related disorders, where PGE₁ is an effective and safebronchodilator and anti-inflammatory agent and is likely to have aparticularly desirable effect both in dilating airways and, in thelonger term, suppressing the airway inflammation that is now recognisedas a major factor in asthma

(b) cardiovascular disorders associated with atherosclerosis, and/orelevated cholesterol, and/or hypertension, and/or excessive plateletaggregation

(c) rheumatoid arthritis, osteoarthritis, dermatitis and otherinflammatory disorders

(d) cancer

Uses also extend to cosmetic or skin care preparations and also to foodsof any type but particularly nutritional supplements.

The particular valve of ascorbyl DGLA is the provision at the same timeand in precisely the same place both the immediate substrate, DGLA, forPGE₁ biosynthesis and a stimulating agent, ascorbate which will enhancethe conversion of the substrate DGLA to PGE₁. As far as we are aware thecompound ascorbyl-DGLA has never previously been described.

The ester may be administered orally, enterally or parenterally incapsules, tablets, sachets, solutions, emulsions, powders, liposomes orother forms in doses of 0.1 mg to 50 g per day, preferably 10 mg to 10 gand very preferably 100 mg to 5 g per day. The ester may also be appliedtopically in creams, ointments, lotions, emulsions, pessaries,suppositories, sticks or other appropriate forms in which the compoundis present in a concentration of 0.001% to 50%, preferably 0.1% to 20%and very preferably 1% to 10% by weight. Similar concentrations may beused to deliver aerosols, liposomes or other appropriate deliverysystems which will ensure delivery of the drug directly to the airways.

A particular appropriate formulation is for the ester to be dissolved ordispersed in free fatty acids or triglycerides in which one or more ofGLA, DGLA and/or the further anti-inflammatory fatty acid EPA is animportant constituent preferably 5% or more by weight. Particularlysuitable triglycerides are ones containing 1, 2 or 3 moieties selectedfrom GLA, DGLA and EPA.

SYNTHESIS EXAMPLE The Preparation of Ascorbic acid6-(z,z,z-octadeca-6,9,12-trienoate)

Ascorbyl GLA; Ascorbyl DGLA may be Prepared in the Same Way

Hydrogen chloride gas (2.0 g) was bubbled into N,N-dimethyl acetamide(26.5 ml) at 0° C. To the resultant slurry was added a slurry ofascorbic acid (9.69 g) in dichloromethane (13.25 ml) and the mixture wasstirred at 0° C. until solution occurred. To this solution at 0° C.under nitrogen, was added z,z,z-octadeca-6,9,12-trienoyl chloride (14.8g) over a period of 4 hours and the resulting mixture was allowed tostand at the above temperature for 18 hours and room temperature for 1hour. On cooling to 0° C., ethyl acetate (200 ml) and water (100 ml) wasadded and the mixture stirred for 1 hour. The organic layer was washedwith brine (5×100 ml), dried (Na₂SO₄) and evaporated at 50° C./10 mmHgthen 50° C./0.1 mm/4 hours to give ascorbic acid6-[(z,z,z)-octadeca-6,9,12-trienoate] (18.25 g, 88%) as a pale yellowwax.

Use Examples

1. Tablets containing 50, 100, 250, 500 or 750 mg of Ascorbyl GLA orAscorbyl DGLA either as such or with an appropriate excipient.

2. Soft gelatin or hard gelatin capsules containing 50, 100, 250 or 500mg Ascorbyl GLA or Ascorbyl DGLA dissolved in free fatty acids enrichedin GLA, DGLA or EPA or in triglycerides in which 1, 2 or 3 of themoieties are selected from GLA, DGLA or EPA.

3. Emulsion, powders, liquids, slurries, or solutions for oral, enteralor parenteral administration of Ascorbyl GLA or Ascorbyl DGLA in aconcentration as referred to herein.

4. Ointments, creams, lotions, shampoos, or other appropriateformulations for the topical application of Ascorbyl GLA or AscorbylDGLA in a concentration as referred to herein.

5. Liposomes made using either phospholipids or glycolipids, for theoral, topical, parenteral or direct airway delivery of Ascorbyl-DGLA.

6. Sprays, suspensions, inhalers or other respiratory delivery systemscontaining Ascorbyl-DGLA.

What is claimed is:
 1. A method of providing optimum conditions for prostaglandin E₁ synthesis comprising orally administering to a patient an amount sufficient to increase prostaglandin E₁ synthesis of an oral tablet or capsule consisting essentially of an ascorbic-6-acid ester of gamma-linolenic acid or an ascorbic-6-acid ester of dihomo-gamma-linolenic acid optionally with a pharmaceutically acceptable carrier or diluent.
 2. A method of treating asthma, a cardiovascular disorder associated with atherosclerosis, elevated cholesterol, hypertension, excess platelet aggregation, rheumatoid arthritis, osteoarthritis, dermatitis or cancer, comprising orally administering to a patient in need of said treatment an amount sufficient to treat atherosclerosis, elevated cholesterol, hypertension, excess platelet aggregation, rheumatoid arthritis, osteoarthritis, dermatitis or cancer of an oral tablet or capsule consisting essentially of an ascorbic-6-acid ester of gamma-linolenic acid or an ascorbic-6-acid ester of dihomo-gamma-linolenic acid optionally with a pharmaceutically acceptable carrier or diluent.
 3. A method of providing optimum conditions for prostaglandin E₁ synthesis comprising parenterally administering to a patient an amount sufficient to increase prostaglandin E₁ synthesis of a parenteral composition consisting essentially of an ascorbic-6-acid ester of gamma-linolenic acid or an ascorbic-6-acid ester of dihomo-gamma-linolenic acid optionally with a pharmaceutically acceptable carrier or diluent.
 4. A method of treating asthma, a cardiovascular disorder associated with atherosclerosis, elevated cholesterol, hypertension, excess platelet aggregation, rheumatoid arthritis, osteoarthritis, dermatitis or cancer, comprising parenterally administering to a patient in need of said treatment an amount sufficient to treat atherosclerosis, elevated cholesterol, hypertension, excess platelet aggregation, rheumatoid arthritis, osteoarthritis, dermatitis or cancer of a parenteral composition consisting essentially of an ascorbic-6-acid ester of gamma-linolenic acid or an ascorbic-6-acid ester of dihomo-gamma-linolenic acid optionally with a pharmaceutically acceptable carrier or diluent.
 5. The method of claim 1, 2, 3 or 4 wherein gamma-linolenic acid or dihomo-gamma-linolenic acid in free fatty acid or triglyceride form are also administered.
 6. The method of claim 1, 2, 3 or 4 wherein 0.1 to 50 g of the ester is administered daily.
 7. The method of claim 1, 2, 3 or 4 wherein 10 mg to 10 g of the ester is administered daily.
 8. The method of claim 1, 2, 3 or 4 wherein 100 mg to 5 g of the ester is administered daily.
 9. The method of claim 1, 2, 3 or 4 wherein an oil containing at least 5% by weight of gamma-linolenic acid, dihomo-gamma-linolenic acid or an essential fatty acid in free fatty acid form or triglyceride form is also administered. 